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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prophylactic insulin therapy prevents IDDM in spontaneous animal models of the disease and has shown promise in preventing the disease in humans. Although large clinical trials have been formed to use this therapy, a comparative analysis of the efficiency of different pharmaceutical forms and doses of insulin in preventing IDDM has not been performed, and the mechanism underlying the observed prevention of disease is unknown. In the NOD-scid/scid adoptive transfer model of IDDM (10(7) new-onset NOD splenocytes injected intravenously into 6- to 8-week NOD/scid-scid recipients; insulitis develops at 6-9 days post-transfer and 100% IDDM by 32 days post-transfer), life-table (log-rank) analyses revealed that IDDM can be delayed (compared with insulin-free diluent, once daily, n = 8) with equivalent efficiency by prophylactic administration (-9-50 days post-transfer) of high (metabolism-altering) doses of short-acting (0.5 U, once daily, regular, n = 13) or long-acting (0.5 U, once daily, ultralente, n = 9) insulin as well as non-metabolism-altering low-dose insulin (0.02 U, once daily, regular, n = 8). Furthermore, IDDM was delayed with somatostatin (0.2 microgram, twice daily, n = 11), an agent that suppresses endogenous insulin production. No significant difference was seen between the preventative effects of these agents. In an assessment of when therapies can be initiated and still maintain clinical efficiency, only prophylactic somatostatin therapy delayed IDDM (n = 10, P = 0.02) when initiated at 14 days post-transfer, whereas the short-acting insulin regimen did not retard the onset of IDDM (n = 8, P = 0.25) compared with diluent-treated controls. The 24-h urinary C-peptide levels were significantly reduced with short-acting (-56%, P = 0.01) and long-acting (-67%, P = 0.02) insulin products and somatostatin (-59%, P = 0.02) compared with diluent-treated controls. These results indicate that both immunological and metabolic (i.e., beta-cell rest) factors may contribute to the beneficial effects of prophylactic insulin therapy.
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PMID:Immunological and metabolic effects of prophylactic insulin therapy in the NOD-scid/scid adoptive transfer model of IDDM. 854 66

The autoimmune nature of insulin-dependent diabetes mellitus (type 1 diabetes) has been definitively established during the past ten years only, owing essentially to the development of the NOD and the BB rat models. Three of the four criterias required for defining an autoimmune disease have been demonstrated in these animal models. IDDM is accompanied by immunological stigmatas including circulating autoantibodies and insulitis (lymphocytic infiltration of the islets of Langerhans), it is attenuated or prevented by immunosuppressors and it is transferable from diabetic to non-diabetic mice or rats, via T lymphocytes. Only the fourth criterium, namely the induction of the disease by immunization with an autoantigen, has so far not been met. As is the case for many, if not most, autoimmune diseases, the pathogenesis of IDDM is, however, far from being totally understood. Many aspects including the circumstances favoring escape from self-tolerance, the role of the genetic background, the nature of the pancreatic antigens involved in the initiation and perpetuation of the disease, the effector mechanisms responsible for the elimination of the insulin cells and, most importantly, the conditions for restoring tolerance are at the forefront of immunopathologists' concerns. We provide in this review an account of the present situation in these different areas of research. There is no doubt that a cure or a prevention of the disease will be available in the forseeable future. Experiments on animal models have already initiated several clinical trials and epidemiological studies, and this is probably only the beginning of a long list.
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PMID:The contribution of animal models to the understanding of the pathogenesis of type 1 diabetes. 855 97

Central to the autoimmune pathogenesis of IDDM in NOD mice is the MHC class II region. In all models studied to date, expression of NOD MHC class II genes is essential for disease development suggesting a crucial role for I-ANOD-restricted presentation of autoantigen. Protection has been afforded by transgene incorporation of other non-NOD class II genes and many models have been proposed to account for this effect. It is now clear that protection is not achieved by deletion or permanent silencing of all autoreactive T cell clones. It also appears that expression of these genes is required both intra- and extrathymically. It still remains to be determined what role these genes may have in the various compartments and how the autoreactive cells are held in check in protected NOD transgenic mice. Currently, the most likely explanation is that intrathymic expression of non-NOD class II genes is required for the positive selection of class II-restricted immunoregulatory T cells, while peripheral expression is necessary to bring about the interaction of these cells in a tricellular complex with NOD autoantigen-specific T cells and APCs, so that the response can be deviated to a nonpathogenetic one. Whether this process is active or passive is not known.
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PMID:Influence of T lymphocytes and major histocompatibility complex class II genes on diabetes susceptibility in the NOD mouse. 860 25

The common class I alleles (e.g., Kd and Db) within the H2g7 major histocompatibility complex (MHC) clearly contribute to autoimmune IDDM in NOD mice, but the mechanism by which this occurs has been controversial. One laboratory has reported that the peptide transporter encoded by the Tap1 gene within H2g7 is defective, and this contributes to IDDM by impairing MHC class I-mediated antigen presentation. If true, defective MHC class I-mediated antigen presentation should segregate with the H2g7 haplotype. NOD mice, related congenic stocks, and other control strains were used to test this hypothesis. H2g7-positive strains did not differ from those expressing other MHC haplotypes in ability to present MHC class I-restricted H3aa or H3ab minor histocompatibility (H) antigens to cytotoxic T-lymphocytes (CTL). The H2g7 haplotype was found to have a reduced capacity to mediate MHC class I-restricted presentation of the H47a minor H antigen. However, MHC class I-restricted presentation of H47a was found to be Tap independent. NOD mice and control strains also did not differ in ability to activate adenovirus-specific MHC class I restricted CTL. Thus, the H2g7 haplotype is not characterized by a Tap gene defect that only impairs the inductive phase of the immune response. In addition, MHC class I-restricted presentation of either minor H or adenoviral antigens was equivalent in male and female NOD mice. Therefore, while the class I alleles of the H2g7 haplotype exert diabetogenic functions in NOD mice, this is not elicited through a Tap gene defect. The absence of female-specific Tap gene defects also indicates this cannot account for the reduced male incidence of IDDM in some NOD mouse colonies.
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PMID:MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell responses in autoimmune diabetes-prone NOD mice. 866 41

IDDM results from immune-mediated destruction of insulin-producing pancreatic beta-cells in individuals genetically susceptible for the disease. There is evidence that the 65-kDa isoform of GAD plays a critical role in the induction of autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what beta-cell antigens autoreactive lymphocytes become activated during early disease. We conducted a prospective study from birth, BABY-DIAB, among children of mothers with IDDM or gestational diabetes or fathers with IDDM, and we investigated the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). Of 1,019 children included at birth, we have currently followed 513 to the age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At birth, all antibody specificities were frequent in newborns of diabetic mothers but not fathers and are suggested to be transplacentally acquired because they are strongly correlated with antibody levels in their diabetic mothers. In early childhood, antibody levels were <99th percentile of control subjects in the majority of children. However, 37 children exhibited elevated antibody levels; these were most frequently detected at the age of 2 years. The antibody prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8% for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers were positive for at least one antibody more frequently than were children of diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%). There was no specific sequence in the appearance of positive autoantibodies, but 13 (35%) antibody-positive cases already had more than one ICA before the age of 2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5 years. The presence of multiple antibodies confers high risk for the future development of diabetes; three of six children who exhibited positive antibody responses to all four antibodies tested and another child with two positive antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5 years. We conclude that loss of tolerance to beta-cell autoantigens and appearance of autoimmune phenomena occur very early in life in individuals with genetic susceptibility for IDDM. Screening programs to identify candidates for disease-prevention therapies can therefore be focused on this young age-group, in whom the disease process may be less advanced and who may therefore be best suited to such therapies.
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PMID:Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. 866 50

The NOD mouse is an animal model of IDDM that shows many of the characteristics of human IDDM. It has been proposed that beta-cell destruction in IDDM progresses over time in a linear manner. Recently, we and others have demonstrated that T helper type 1 (Th1) cells have pathogenic roles in the NOD model and proposed that cytokine balances change as the disease progresses. However, it has not been demonstrated how or when the cytokine balances change or how the beta-cell destruction progresses. We have recently demonstrated that the cytokine profiles of CD45RB(low) CD4+ cells correlate either with their pathogenic or with their protective roles in the NOD mouse. To further analyze this apparent correlation between the shift in cytokine level and IDDM, we examined the anti-CD3-induced cytokine profiles of this subset from NOD mice of various ages compared with that from age-matched I-Ak transgenic NOD and BALB/c mice as controls. A significantly higher ratio of anti-CD3-induced interferon-gamma/interleukin-4 was found in diabetic NOD mice (P < 0.0001) but not in age-matched nondiabetic NOD mice. This cytokine ratio did not change significantly until the onset of diabetes in NOD mice. Based upon these results, we propose that IDDM in the NOD mouse progresses as a predominant inflammatory beta-cell dysfunction without actual beta-cell destruction until late in the disease process. This supports the possibility that late-stage immunotherapy may preserve islet beta-cell mass.
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PMID:Beta-cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. 869 Jan 53

The role of T-cells in the pathogenesis of IDDM has been an area of much interest, and investigators have recently acquired new tools for studies on T-cells with the advent of T-cell clones that are reactive with islet antigens. Derived from NOD mice, diabetogenic T-cell lines and clones have for the most part been CD4+ and T-helper 1 (Th1)-like in their cytokine production. Some CD8+ cytotoxic clones have also been reported, although these have generally not transferred diabetes in the absence of CD4+ T-cells. The T-cell clones that have been described can also be separated on the basis of their antigen reactivity. While many of the T-cell lines and clones described react with islets, isolated islet cells, or islet membrane preparations, others have known antigen specificities, reacting with defined islet cell proteins such as insulin, GAD, and heat shock proteins. Particularly in the case of insulin-reactive clones, diabetogenicity has also been demonstrated. In light of the many possible T-cell reactivities that may arise from the islet lesion, the question of whether there is a dominant initiating antigen is a particularly intriguing one.
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PMID:Diabetogenic T-cell clones. 882 63

Recently, the synthetic immunomodulator Linomide (quinoline-3-carboxamide, LS 2616) was reported to prevent IDDM and insulitis in NOD mice. The mechanism for this protective effect is not known. The cytokine interleukin 1 (IL-1) may be a pathogenetic factor in the initial destruction of the beta-cells leading to IDDM. This study was undertaken to investigate the influence of Linomide on IL-1beta induced diabetogenic and hormonal changes in the rat in vivo, and on IL-1beta mediated synthesis of NO and inhibition of insulin secretion in isolated islets of Langerhans ex vivo. Normal male Wistar Kyoto rats received 4.0 microg/kg of recombinant human IL-1beta (rhIL-1beta) i.p. daily for 5 days with or without Linomide (8-9 mg/kg/day) in the drinking water. Litters of neonatal Wistar rats were pretreated for 3 days with injections of 10 mg/kg of Linomide i.p., and pancreatic islets of Langerhans were isolated for ex vivo studies. Linomide alone caused significant hypercorticosteronemia, hypoglucagonemia, lymphopenia and neutrophilia. Linomide had no effect on IL-1beta induced hyperglycemia, hyperglucagonemia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prevent rhIL-1beta mediated reduction in insulin secretion or increase in NO synthesis ex vivo. In conclusion, Linomide does not seem to exert its protective effect on IDDM development via inhibition of interleukin 1 action on islet insulin release or NO production, but the increase in plasma corticosterone may contribute to the understanding of the immunomodulatory effects of Linomide.
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PMID:Linomide increases plasma corticosterone in normal rats, but does not prevent the inhibitory action of IL-1 on beta-cells in vivo or ex vivo. 891 32

Type 1 diabetes mellitus (IDDM) is a disease caused by the autoimmune destruction of insulin-producing pancreatic beta cells that takes place in genetically predisposed individuals. The results of the studies performed so far during the search for "the target antigen" in beta cell autoimmunity have indicated that, unlike many autoimmune disorders, type 1 diabetes appears to be the result of an autoimmune response to a multiplicity of autoantigens. Autoantibodies and autoreactive T lymphocytes reacting with islet target molecules of protein or glycolipid nature have been shown in the circulation of individuals and of animal models of type 1 diabetes (NOD mouse and BB rat) before and at the onset of the disease. In the present article we have reviewed the data available on the antigenic determinants in type 1 diabetes, with particular reference to those recognized by autoantibodies which represent the best available predictive marker of future disease development in large scale screening studies.
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PMID:Antigenic determinants in type 1 diabetes mellitus. Review article. 898 39

IDDM is caused by autoimmune destruction of insulin-producing beta cells of the pancreas in genetically susceptible individuals. Although the incidence and prevalence if IDDM in Japan are much lower than those in Caucasian countries, the recurrence risk in siblings of IDDM probands is much higher than the population prevalence, indicating that IDDM is clustered in families even in Japan, where the incidence of the disease is the lowest in the world. The higher concordance rate in monozygotic twins than in dizygotic twins indicates that genetic factors contribute to the familial clustering of IDDM in Japan. Analysis of the HLA region revealed that susceptibility genes (IDDM1) consist of multiple components, those in class II DR and DQ regions and another in the class I region. Analysis in NOD mice, an animal model of IDDM, supports this observation: susceptibility genes (Idd1) are mapped to class II A and E regions, but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Studies in both humans and an animal model will clarify the genetic components of IDDM, facilitating prediction of the disease and the development of effective strategies for its prevention.
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PMID:Genetics of insulin-dependent diabetes mellitus. 907 99


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